Protein kinase CK2 or casein kinase 2 (CK2) is a highly conserved and ubiquitously expressed serine/threonine protein kinase, which exists as a tetrameric complex of two catalytic (α or α′) and two regulatory (β) subunits. CK2 has broad function, which includes controlling cell growth, proliferation, and evasion of apoptosis by phosphorylation of a range of substrates in critical cellular signaling pathways including P13K (phosphatidylinositol 3-kinase)/AKT (protein kinase B), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and Wnt (wingless type MMTV integration site family. See, e.g. Ruzzene et al. Biochim. Biophys Acta (2010) 1804: 499-504; Di Maira et al. Cell. Mol. Life Sci. (2009) 66: 3363-3373; Dominguez, I. et al. Cell. Mol. Life Sci. (2009) 66: 1850-1857.
Elevated CK2 activity caused by overexpression of the enzyme (notably but not necessarily limited to the CK2 α and α′ subunits) has been shown to correlate with tumor aggressiveness and tumor growth. In particular, CK2 overexpression has been demonstrated in hematological malignancies, including chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and multiple myeloma. Elevated CK2 activity promotes tumorigenesis via the regulation of the activity of various oncogenes and tumor suppressor proteins. Hence, not until recently, CK2 is considered as a possible target in cancer chemotherapy. CK2 has also been demonstrated to increase a cell's oncogenic potential by sensitizing a cell to transformation by other oncogenic proteins. See, Landesman-Bollag et al. Oncogene (2001) 20: 3247-3257.
Although CK2 is generally regarded as a constitutively active kinase, more recent evidence suggests that the enzyme can regulate and be regulated by growth factors such as IL-6 and epidermal growth factor (EGF). Additionally, a variety of ATP-competitive, small-molecule inhibitors of CK2 have been identified. These include various polyhydroxylodated aromatic compounds (such as emodin and quercetin), polyhalogenated compounds (such as DRB (5,6-dichlororibofuranosylbenzimidazole) and TBB (4,5,6,7-tetrabromo-1H-benzotriazole), as well as the indolo-[1,2-a]quinazoline derative IQA. Inhibitors of CK2 that are useful for treating certain types of cancers are described in International Patent Application Nos. PCT/US2007/077464, PCT/US2008/074820, PCT/US2009/35609 and PCT/US2010/56712.
Through the use of small molecules, dominant negative over-expression of kinase inactive mutants, anti-sense methods, and small interfering RNA molecules (siRNA), complete eradication of the PC3 human prostate cancer tumor in tumor-bearing mice has been demonstrated.
Many of the existing CK2 inhibitors, including emodin, coumarins, TBB, quinazolines, DRB and quercetin, while useful for laboratory studies, lack the potency, physiochemical and pharmacological properties required to be a clinically useful chemotherapeutic agent. Therefore, a significant need remains for compounds that effectively and specifically inhibit CK2 activity in a clinical setting, as well as for associated compositions and methods. The present invention satisfies this need and provides further related advantages.